The goal of this project is to address the role of a subset of histone deacetylase (HDAC) enzymes, class I HDACs, in the control of diastolic heart failure. Each year more than 600,000 cases of heart failure (HF) are diagnosed in the United States, adding to the more than 5 million adults with this condition; costs of care are estimated at $34.8 billion per year. About half of these patients have heart failure with preserved ejection fraction (HFpEF), or diastolic heart failure. Aging and hypertension are major risk factors for the development of HFpEF. Over the last two decades, systolic heart failure (sHF) patients have seen clinical benefits through pharmacological management; unfortunately, standard-of-care sHF medications have failed to show efficacy in large clinical trials in patients with HFpEF. Histone deacetylases (HDACs) catalyze removal of acetyl groups from lysine residues in a variety of proteins. The 18 mammalian HDACs are encoded by distinct genes and fall into four classes (I, II, III and IV). Broad-spectrum, 'pan' inhibitors of HDAC catalytic activity are marketd for cancer. Our preliminary data demonstrate that pan-HDAC inhibition is profoundly protective in a rodent model of HFpEF induced by chronic hypertension. HDAC inhibition blocked cardiac hypertrophy and fibrosis, improved diastolic cardiac function, and prolonged lifespan even in the face of sustained hypertension. In subsequent studies we determined that class I HDAC- selective inhibition blocks cardiac fibrosis through a mechanism associated with induction of anti-inflammatory regulatory T cells (Tregs). These results suggest an unanticipated application for isoform-selective HDAC inhibitors for the treatment of human HFpEF. This proposal is designed to address the overall hypothesis that class I HDACs promote diastolic dysfunction in the aging heart by triggering ventricular inflammation and fibrosis. Results from these studies should provide novel insights into the molecular basis of diastolic heart failure, and could form the foundation for innovative approaches to drug discovery for HFpEF based on isoform- selective HDAC inhibition.